Watchful Waiting for Prostate Cancer: An Acceptable Option for Older Men?
Key words: Prostate cancer, watchful waiting, active surveillance, cancer screening, PSA testing, prostate biopsy.
It is well known by patients and clinicians that prostate cancer is the most common malignancy among older men in the United States.1 Studies have shown that 50% of men between the ages of 70 and 80 years have histological evidence of malignancy.2 The probability of developing histological evidence of prostate cancer and the probability of developing clinically significant disease are, however, very different. Patients have only a 9.5% chance of developing clinically significant disease at the age of 50 years compared with a 42% chance of showing histological evidence of malignancy at the same age.3 This discrepancy raises a dilemma for physicians caring for patients who have or might develop prostate cancer: How should elderly men with histology demonstrating malignancy—but no overt symptoms of the disease—be treated? The list of treatment options for prostate cancer is long, and the selection of the most appropriate option for any given patient depends on a number of factors, including patient age, life expectancy, and Gleason score. In this article, we examine the diagnostic modalities that are used to make a diagnosis of prostate cancer, including prostate-specific antigen (PSA) screenings and prostate biopsies. We also look at the treatments and factors to consider when deciding on treatment or watchful waiting, also known as active surveillance.
The argument has been made that we are detecting clinically silent disease now that would never have been detected in the past as a result of the increasing use of PSA testing.4 An advantage of PSA testing is that it is a simple blood test, but its simplicity is also its downfall. The test lacks specificity, and approximately two of every three men with elevated PSA levels who undergo a prostate biopsy are found not to have prostate cancer.5,6 In addition, as men age, their PSA levels increase when the prostate undergoes benign hyperplastic changes.7 Because it is thought that the prostate gland enlarges in all men, provided they live long enough for this to occur, one can understand the problem with using PSA as a “screening” test for prostate cancer. Although PSA-based screening reduces the rate of death from prostate cancer by up to 20%, it is associated with a high risk of overdiagnosis.8 The European Randomized Study of Screening for Prostate Cancer found that, to prevent only one death from prostate cancer, 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated.8 Based on such findings, the US Preventive Services Task Force (USPSTF) has stated in its recently updated recommendations that PSA screening results in little, if any, mortality benefit, and it therefore no longer recommends that men of any age undergo PSA screenings.9 As would be expected, this move has generated considerable controversy.
Once prostate cancer is suspected, often as the result of a combination of elevated PSA levels and abnormal findings on a digital rectal examination, a prostate biopsy is the next test to be performed. A systematic review published in 2003 suggested that the most widely accepted indication for prostate biopsy is a PSA value above 4.0 ng/mL.10 The goal of prostate biopsy, however, is not to detect each and every cancer, but to detect cancer that has the potential to cause harm.11 Yet despite the known limitations of PSA testing, it has been reported that we are performing more prostate biopsies than ever before.12 Of the approximately 1 million prostate biopsies performed annually in the United States, only an estimated 25% of them actually detect the presence of cancer.9
Prostate biopsy is used to determine a patient’s Gleason score (grading system used to determine the prognosis of a man with prostate cancer), and in combination with other clinical factors, including a patient’s PSA level, is used to determine a patient’s clinical stage. There is abundant evidence for the Gleason score, for instance, being correlated with risk of death from prostate cancer.13 A study by Albertsen and colleagues14 investigated long-term outcomes of 767 men with localized prostate cancer diagnosed between 1971 and 1984. The authors found that in patients aged 55 to 74 years, only 7% and 11% of those with Gleason scores of 2 to 4 and 5, respectively, died of prostate cancer; however, 27%, 45%, and 66% of men with biopsy Gleason scores of 6, 7, and 8 to 10, respectively, died of prostate cancer.14 Men with a Gleason score of 5 or 6 have an intermediate risk of dying of their prostate cancer.
Risk stratification is key to selecting the appropriate treatment for the patient, with some men being offered radical treatment (eg, radical laparoscopic or radical robotic prostatectomy), some being offered radiation therapy, some being offered medical or hormonal treatments, and others being offered less radical treatments, such as watchful waiting, which involves the close monitoring of a patient’s condition without medical intervention or therapy until the condition becomes symptomatic.
There is much controversy surrounding the treatment of localized prostate cancer, as there is a paucity of randomized clinical trials demonstrating the benefit of one treatment strategy over another. Often, the decision hinges on whether the cancer needs to be treated radically or whether a more cautious approach can be adopted, with the knowledge that many men are more likely to die with prostate cancer than of it. Factors that increase the likelihood of the former occurring are advanced age and the presence of significant additional comorbidities. In many elderly men, the decision is made to adopt a strategy of watchful waiting, and this approach appears to be sensible for those who are at low risk of death from their prostate cancer.
A 2011 study by Bill-Axelson and colleagues,15 which compared the rates of death due to prostate cancer in patients treated with radical prostatectomy versus those treated with watchful waiting, unsurprisingly found that radical removal of the prostate gland was associated with a reduction in the rate of death from prostate cancer. These results are, of course, to be expected and do not necessarily mean that clinicians should favor surgical management over watchful waiting, particularly in older men. The considerable risks of surgical procedures, in combination with the often short life expectancy of elderly men, render it unlikely that these patients will see any benefit from undergoing surgery. As a result, the noninvasive watchful waiting approach is often more appropriate for these patients, and when examining the data from the aforementioned study more closely, it becomes apparent that the incidence of death from any cause was statistically the same between men treated surgically and those who used a watchful waiting strategy.15
Since there are no tests available that can clearly define the aggressiveness of prostate cancer, physicians should offer advice to their patients based on medical evidence and help them reach a decision they (the patients) are comfortable with, which also includes the decision to opt for watchful waiting. There are various factors that can help physicians provide sound advice to a patient, including the patient’s age, PSA level at diagnosis, Gleason score, percentage of the biopsy that is positive for prostate cancer, number of cores that are positive, presence of comorbidities, and the overall life expectancy. Also, as stated previously, individuals must consider the treatment side effects when making their decision, which may include urinary incontinence, erectile dysfunction, and complications from surgery or radiation.
Unlike many other types of cancer, most prostate cancer grows very slowly. Although 17 of 100 men in the United States will get prostate cancer, only three of these 17 will die of prostate cancer, which means that 97 of 100 men will die of something other than prostate cancer.16 Because prostate cancer tends to be a slow-growing tumor, men with prostate cancer do not have to make a decision regarding treatment quickly. In fact, most patients can safely wait weeks or even months before reaching a decision. Further, slow-growing prostate cancer does not normally cause symptoms, so it is possible to have prostate cancer for years without ever knowing it. In cases when prostate cancer is discovered very early because of a PSA test, symptoms usually do not appear for at least 10 years. Thus, if a patient’s prostate cancer is small and slow-growing, he may have a few years to decide whether to start treatment or to continue with the watchful waiting approach. What follows is a closer review of three of the most important factors physicians should consider when deciding on a treatment strategy. These include age, life expectancy, and Gleason score.
The medical community generally accepts that older patients with localized prostate cancer probably do not need to consider treatment, unlike younger patients.17 In the aforementioned study by Bill-Axelson and colleagues,15 early surgery did not significantly improve survival in men who received a prostate cancer diagnosis after age 65. Watchful waiting appears to work as well as prostatectomy and radiation therapy for most men who are older than 65 years and have early-stage prostate cancer (stages I and II). For younger men (<65 years) with clinically localized prostate cancer, treatment with surgery may help to increase their longevity.18,19
There is widespread agreement in the international community that one of the most important factors to consider when making recommendations to patients about treatment is their life expectancy.11,20 When a man’s life expectancy is relatively long (≥10 years), localized prostate cancer (stages I and II) can be a cause of significant morbidity and mortality. When estimated life expectancy is shorter, however, because of advanced age or the presence of significant comorbidities that are likely to reduce life expectancy (eg, congestive heart disease, aortic stenosis), “competing hazards for mortality” reduce the chance that a man will experience disease progression or die of prostate cancer.18
The Gleason score grades tumors on the basis of how abnormal they look when the tissue is examined under a microscope. The more abnormal the cells appear, the more likely they are to grow quickly and to spread to other parts of the body. A grade below 4 generally means that cancer cells look similar to normal cells, grades 5 to 7 fall under the intermediate range, and grades 8 to 10 indicate aggressive growth. Patients with lower Gleason scores are better candidates for watchful waiting than patients with higher scores (ie, Gleason scores >6).17
Monitoring Patients Who Choose Watchful Waiting
Research has shown that the best candidates for watchful waiting are men older than 65 years with PSA levels below 10 ng/mL, Gleason scores no higher than 6, fewer than 50% of any core involved in prostate cancer, fewer than 33% of all cores containing cancer, and lack of other comorbid conditions that suggest a life expectancy of less than 10 years (eg, heart disease, hypertension, dyslipidemia, diabetes).17 Therefore, these are the patients for whom watchful waiting may be ideal.
There is no standardized definition in the literature of what active surveillance for prostate cancer entails, and numerous monitoring protocols have been followed, all with different combinations of periodic PSA testing, digital rectal examinations, rebiopsy, and/or imaging studies. Predictors that a patient received no initial active treatment generally included older age, presence of comorbidities, lower Gleason score, lower tumor stage, lower diagnostic PSA level, and lower risk of disease progression.21
Studies have shown that the faster it takes for a patient’s PSA level to double from the nadir level (a process called doubling time), the more aggressive his cancer.22,23 Therefore, PSA continues to be the primary marker of whether the disease is stable, spreading, or responding to treatment. In addition to periodic PSA screenings, it may be prudent to perform an annual prostate biopsy, so that a patient receives appropriate treatment as soon as there is evidence that the cancer is progressing, but well before it becomes a high-risk tumor.
Advantages of Watchful Waiting
Prostate cancer treatments, such as surgery, radiation, and hormone therapy, can cause serious side effects, including bladder, bowel, and erection problems. With watchful waiting, men who have low-risk prostate cancer can wait to start other treatments. While some will never need more treatment, others can postpone experiencing any side effects until tests show that their cancer is progressing.
If an older patient chooses watchful waiting, it is important to inform him that his cancer can spread and become incurable, but that this type of progression in older men is uncommon. Regular checkups should be encouraged, as they increase the odds of determining in a timely manner that the cancer is growing, enabling the patient’s cancer to still be treated at an early stage, when treatments are more successful. The risks associated with watchful waiting include a small chance that the cancer may grow quickly and spread.
Prostate cancer tends to be a slow-growing tumor. Therefore, active surveillance with delayed intervention appears to be a viable option for carefully selected older men (>65 years), including those with PSA levels below 10 ng/mL, Gleason scores no higher than 6, and the lack of comorbid conditions that limit life expectancy, such as heart disease and diabetes. Although there are no guidelines as to what active surveillance should entail, periodic PSA testing and annual prostate biopsies can help clinicians detect spread before the tumors become high-risk and contribute to mortality.
1. Crawford ED. Epidemiology of prostate cancer Urology. 2003;62(suppl 6A):3-12.
2. Carter HB, Piantadosi S, Isaacs JT. Clinical evidence for and implications of the multistep development of prostate cancer. J Urol. 1990;143(4):742-746.
3. Scher HI, Isaacs JT, Zelefsky MJ, et al. Prostate cancer. In: Abeloff MD, Armitage JO, Lichter, Niederhuber JE, eds. Clinical Oncology. 2nd ed. New York, NY: Churchill Livingstone; 2000:1823-1884.
4. Hall IJ, Taylor YJ, Ross LE, Richardson LC, Richards TB, Rim SH. Discussions about prostate cancer screening between U.S. primary care physicians and their patients. J Gen Intern Med. 2011;26(10):1098-1104.
5. Selley S, Donovan J, Faulkner A, Coast J, Gillatt D. Diagnosis, management and screening of early localized prostate cancer. Health Technol Assess. 1997;1(2):i,1-96.
6. Thompson IM, Ankerst DP, Chi C, et al. Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0ng/ml or lower. JAMA. 2005;294(1):66-70.
7. Hamdy FC. Prognostic and predictive factors in prostate cancer. Cancer Treat Rev. 2001;27(3):143-151.
8. Schröder FH, Hugosson J, Roobol MJ, et al; ERSPC Investigators. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360(13):1320-1328.
9. Moyer VA. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157(2):120-134.
10. Matlaga BR, Eskew LA, McCullough DL. Prostate biopsy: indications and technique. J Urol. 2003;169(1):12-19.
11. National Institute for Health and Clinical Excellence (United Kingdom). Prostate cancer: diagnosis and treatment. 2008. www.nice.org.uk/nicemedia/pdf/CG58NICEGuideline.pdf. Accessed September 11, 2012.
12. Bostwick DG, Meiers I. Prostate biopsy and optimization of cancer yield. Eur Urol. 2006;49(3):415-417.
13. Johansson JE, Holmberg L, Johannson S, Bergström R, Adami HO. Fifteen-year survival in prostate cancer. A prospective, population-based study in Sweden [published correction appears in JAMA. 1997;287(3):206]. JAMA. 1997;277(6):467-471.
14. Albertsen PC, Hanley JA, Fine J. 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA. 2005;293(17):2095-2101.
15. Bill-Axelson A, Holmberg L, Ruutu M, et al; SPCG-4 Investigators. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2011;364(18):1708-1717.
16. Zelefsky MJ. Cancer of the prostate. In: DeVita VT, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology. 8th ed. vol. 1. Philadelphia, PA: Lippincott Williams and Wilkins; 2008:1392-1452.
17. Dall’Era MA, Cooperberg MR, Chan JM, et al. Active surveillance for early-stage prostate cancer: review of the current literature. Cancer. 2008;112(8):1650-1659.
18. Bill-Axelson A, Holmberg L, Ruutu M, et al; Scandinavian Prostate Cancer Study Group No. 4. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2005;352(19):1977-1984.
19. Lu-Yao GL, Albertsen PC, Moore DF, et al. Outcomes of localized prostate cancer following conservative management. JAMA. 2009;302(11):1202-1209.
20. American Urological Association Foundation. The management of localized prostate cancer: patient guide. 2008. www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines/patient-guides/pc08.pdf. Accessed September 11, 2012.
21. Ip S, Dahabreh IJ, Chung M, et al. An Evidence Review of Active Surveillance in Men With Localized Prostate Cancer. Rockville, MD: Agency for Healthcare Research and Quality (US); 2011. www.ncbi.nlm.nih.gov/books/NBK83054. Accessed December 12, 2012.
22. Antonarakis ES, Keizman D, Carducci MA, Eisenberger MA. The effect of PSA doubling time (PSADT) and Gleason score on the PSA at the time of initial metastasis in men with biochemical recurrence after prostatectomy. J Clin Oncol. 2011;29(suppl 7):abstract 16. www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=104&abstractID=72218. Accessed December 12, 2012.
23. Roberts SG, Blute ML, Bergstralh EJ, Slezak JM, Zincke H. PSA doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer. Mayo Clin Proc. 2001;76(6):576-581.
The authors report no relevant financial relationships.
Address correspondence to:
Neil Baum, MD
3525 Prytania Street
New Orleans, LA 70115